A Glucose/Oxygen-Exhausting Nanoreactor for Starvation- and Hypoxia-Activated Sustainable and Cascade Chemo-Chemodynamic Therapy

Fenton reaction-mediated chemodynamic therapy (CDT) can kill cancer cells via the conversion of H₂ O₂ to highly toxic HO•. However, problems such as insufficient H₂ O₂ levels in the tumor tissue and low Fenton reaction efficiency severely limit the performance of CDT. Here, the prodrug tirapazamine (TPZ)-loaded human serum albumin (HSA)-glucose oxidase (GOx) mixture is prepared and modified with a metal-polyphenol network composed of ferric ions (Fe³⁺ ) and tannic acid (TA), to obtain a self-amplified nanoreactor termed HSA-GOx-TPZ-Fe³⁺ -TA (HGTFT) for sustainable and cascade cancer therapy with exogenous H₂ O₂ production and TA-accelerated Fe³⁺ /Fe²⁺ conversion. The HGTFT nanoreactor can efficiently convert oxygen into HO• for CDT, consume glucose for starvation therapy, and provide a hypoxic environment for TPZ radical-mediated chemotherapy. Besides, it is revealed that the nanoreactor can significantly elevate the intracellular reactive oxygen species content and hypoxia level, decrease the intracellular glutathione content, and release metal ions in the tumors for metal ion interference therapy (also termed "ion-interference therapy" or "metal ion therapy"). Further, the nanoreactor can also increase the tumor's hypoxia level and efficiently inhibit tumor growth. It is believed that this tumor microenvironment-regulable nanoreactor with sustainable and cascade anticancer performance and excellent biosafety represents an advance in nanomedicine.

Keywords: albumin nanoparticles; hypoxia-activated cancer therapy; metal ion interference therapy; metal-phenolic networks; tumor microenvironment.